N, n-disubstituted aminoalkanol esters of alpha, alpha-diacyltoluic acids and their salts



Patented Oct. 13, 1953 N,N DISUBSTITUTED AMINOALKANOL ESTERS F u,a-DIACYLTOLUIC ACIDS AND THEIR SALTS Carl Peter Krimmel, Mundelein, Ill., assignor to G. D. Searle of Illinois & 00., Chicago, 111., a corporation N 0 Drawing. Application March 6, 1951,

Serial No.

Claims. (Cl. 260-294.3)

wherein Ar and Ar' are aryl groups, wherein Alk is an alkylene radical and wherein B is a member of the class comprising dialkylamino radicals and radicals of the type NX which are attached through the nitrogen to the All: radical and in which X is a member of the class comprising alkylene and ethyleneoxyethylene radicals.

In the foregoing structural formula Ar and Ar may represent such lower arylgroups as phenyl, 0-, m-, and p-tolyl, o-, m-, and p-anisyl and the like. The Alk group represents bivalent, saturated, aliphatic hydrocarbon radicals of from two to eight carbon atoms. These radicals are derived from straight-chain or branchedchain aliphatic hydrocarbons and include radicals such as ethylene, propylene, butylene, amylene, and polymethylene radicals such as trimethylene, tetramethylene, pentamethylene, and hexamethylene. Among the radicals which B may represent are dialkylamino radicals of the type NRR'; wherein R and R are such lower alkyl groups as methyl, ethyl, propyl, butyl, amyl, and hexyl; and wherein the propyl,-butyl, amyl, and hexyl groups may be of the straightchain, branched-chain or cyclic type. The radical B may also be a saturated, nitrogen-containing heteromonocyclic radical such as a N-piperidino, N-lupetidino, N-pyrrolidino, and N-morpholino radical.

The organic bases of the foregoing type form salts with a variety of inorganic and strong organic acids including sulfuric, phosphoric, hydrochloric, hydrobromic, sulfamic, citric, lactic, maleic, malic, succinic, tartaric, cinnamic, acetic, oxalic, ascorbic and related They also form quaternary ammonium salts with a variety of organic esters of sulfuric, hydrohalic and aromatic sulfonic acids. Among such esters are methyl chloride and bromide, ethyl chloride, propyl chloride, butyl chloride, isobutyl chloride, benzyl chloride and bromide, phenethyl bromide, naphthylmethyl chloride, dimethyl sulfate, diethyl sulfate, methyl benzenesulfonate, ethyl toluenesulfonate, ethylene chlorohydrin, propylene chlorohydrin, allylbromide, methallyl bromide and crotyl bromide.

The esters of this invention have been found to possess a number of useful therapeutic properties. Thus, they are effective spasmolytics and cardiovascular drugs. They are also effective vasodilators.

The acids which constitute the starting materials for the esters of this invention are prepared by conventional methods, such as that of Drory (Ber. Deut. Chem. Thus, a,a-diphenyl-o-toluic acid, M. P. l61164 0., is prepared by causing o-cyanobenzal chloride, benzene and aluminum chloride to react to obtain o-cyanotriphenylmethane, which is hydrolyzed to the acid with 25% alcoholic potassium hydroxide. The o-cyanobenzal chloride is conveniently obtained by the chlorination of o-tolylnitrile by ultraviolet radiation. In the same manner, starting with m-tolylnitrile and p-tolylnitrile, a,a-diphenyl-m-toluic acid, M. P. -182" C. and a,a-diphenyl-p-toluic acid, M. P. 163-165 C. are obtained.

ma Di o tolylphenylmethane-o-carboxylic acid, M. P. 239-240" 0., is prepared by the reduction of di-o-tolylphthalide with 5% sodium amalgam in ethanol. The phthalide in turn is prepared by the Grignard reaction using o-bromotoluene and phthalic anhydride dissolved in benzene.

My invention is disclosed in further detail by the following examples which are set forth for the purpose of illustrating this invention and which arein no way to be construed as limiting the invention in spirit or in scope. It will be apparent to those skilled in the art that many conventional. modifications in methods, condi- Ges. 24, 2572; 1891).

tions and materials can be adopted without departing therefrom.

In the examples, the temperatures given refer to degrees centigrade C.), the parts by weight the parts by volume to milliliters (ml), tillation in millimeters (mm.) of mercury.

EXAMPLE 1 Z-diethulaminoethyl ester of a,-diPMfl1ll-O- toluic acid Asolution of sodium isopropylate, containing 2.0 g. of sodium, in 200 ml. of isopropanol, is treated with 25.0 g. of a,a-diphenyl-o-toluic acid. To this mixture 14.9 g. of the hydrochloride of 2-chloroethyldiethylamine in 200 ml. of isopropanel are added, and after stirring, and heating at reflux temperature for tour hours, the isopropanol is distilled off under vacuum. The crystalline product is washed with 200 ml. of iso-.

propanol, filtered, and recrystallized from absolute ethanol, using charcoal as a clarifying agent. 18.7 g. of white crystalline hydrochloride are obtained, which melt at 146-148.5 C. It has the structural formula EXAMPL 2 c,a-Diphenyl-o-toluic acid ester of c-hydroryethyl-triethyl ammonium bromide g. of the 2-diethylaminoethyl ester of 11,1- diphenyl-o-toluic acid, prepared as in Example 1, are heated for 3 hours in a pressure bottle with 5.6 g. 0! ethyl bromide and ml. of butanone. After cooling, the crystals are washed with butanone and dried. 5.2 g. of the bromide are thus obtained which on recrystallization from butanone form white flakes melting at 194-196 C. with decomposition. It has the structural formula EXAMPLE 3 Z-diethylaminopropyl ester of a,a-diphenyl-otoluic acid To a. stirred solution of 28.8 g. of a,a-diphenylo-tolulc acid in 500 ml. of anhydrous isopropanol, 15.0 g. of 2-diethylaminopropyl chloride are added in one batch, and the mixture is maintained at reflux temperature for 3 hours. The isopropanol is distilled ofi under vacuum, the residue taken up in water, extracted with ether, and made alkaline. The oily base is extracted with ether, and the extract dried over potassium carbonate. and evaporated. Vacuum distillation oi the residue yields 22.0 g. of a colorless, viscous oil which boils at 225231 C. and 1.1 mm. pressure. To a solution of 12.0 g. of this base in 3 liters of ether, an equivalent of a solution of hydrogen chloride in isopropanol is added with stirring. The hydrochloride is washed with ether, dried, and recrystallized from butanone, to obtain white crystals which melt at -137" has the structural formula EXAMPLE 4 toluic acid C. It

ter of a,a.diphenyl-ostirred refluxing solution of 28.8 g. of

a,a-diphenyl-o-toluic acid in anhydrous isoprofor three hours, moved in vacuo,

cipitated in panol, 15.0 g. of 3-diethylaminopropyl chloride are added in one batch. The mixture is heated after which the solvent is rethe residue taken up in water, the milky solution extracted with ether, made as in Example 3.

clear viscous oil, boiling at 229- 236 C. and 0.5 mm. pressure are obtained,

Washing with yields white crystals melting at 131-133 C.

EXANIPLE 5 The as in Example 3, is preolloidal powder, which ether a,a-Dipenyl-o-toluic acid ester of -hydroxyropyl-triethylammonium bromide 12.0 g. of the 3 u,adlph8IlY1-O-t01lll0 aci and 20 ml. of bu bottle for 3 hours. treatment of the cooled quantity of ether. tals are thus obta 13.1 g. of cream-colored from butanone melt at 148-450 C.

EXAMPLE 6 -diethylaminopropyl ester of d, 5.6 g. of ethyl bromide tanone are heated in a pressure Crystallization is induced by product with a small ined, which on recrystallization 3-di-n-propylaminopropyl ester of a-,a.-

diphenul-o-toluic acid bon tetrachloride are the solid residue Then 15.9 g. of 3-di-n added, and the mixture ture for 3 hours.

neutral material l chloride and 200 ml. of carreflux temperature for two thionyl chloride and the car removed under vacuum and is taken up in 200 ml. of acetone.

-propylaminopropanol are heated at reflux tempera- The acetone is removed-under vacuum, the residue is taken up in water, the

is extracted with ether, and the aqueous layer is made alkaline with potassium hydroxide. The

and the ether extract bonate. The ether is tillation yields 22.3 g o viscous yellow oil boiling at 236 246 mm. pressure.

7.0 g. of this an equivalent 0 chloride in isopropanol is The white cry stirring. filtered, washed uum desiccator. which, on recrys 156158 C.

oily

base are f a 25% slowly added with ether, and dried in a 9.0 g. of crystals are obt tallization from acetone, in

base is extracted with ether, is dried over potassium carevaporated. Vacuum disf the ester in the form of a C. and 0.6

dissolved in ether and solution of hydrogen with stalline precipitate is vacained elt at EXAMPLE 7 Z-diethylaminoethyl ester of a,a-di(o-tolyl) o-toluic acid solution in anhydrous isopropanol. The powdery white precipitate is suction filtered, ether washed, and dried. There is obtained, upon crystallization from butanone, 10.2 g. of a white, water-soluble, crystalline solid melting at; 179180 C. The base has the structural formula EXAMPLE 8 fl-(N-piperzdz'no) ethyl ester of a,adijDheTLyZ- o-toluio acid A stirred refluxing solution of 28.8 g. of a,a-diphenyl-o-toluic acid in 500 ml. of anhydrous isopropanol is treated with 14.8 g. of N-(fl-chloroethyl) piperidine and maintained at reflux temperature for 5 hours. The isopropanol is then distilled oii under vacuum, and the residue taken up in 800 ml. of hot water and filtered. The yellow filtrate is decolorized With charcoal and concentrated. 14.0 g. of white crystals are obtained which melt at 216-217 C.

In the identical manner the ,c-(N-lupetidino) ethyl ester of a,a-diphenyl-o-toluic acid and [3- (N -pyrrolidino) ethyl ester of a,a-diphenyl-otoluic acid are obtained.

EXAMPLE 9 fl-(N-morphoZinmethg Z ester of a,a-di-o-tolylo-toluic acid 31.6 g. of a,a-dio-to1y1-o-to1uic acid are reacted in isopropanol solution with 15 g. of N-(B- chloroethyl) morpholine at reflux temperature for 5 hours. The isopropanol is then distilled oiT. and the residue is purified as in Example 8.

EXAMPLE 10 Z-diethylamz'noethyl ester of a,a-diphenyZ-mtoluic acid ture is diluted with 1000 ether and scratched to filtered and dried. After recrystallization from butanone, 12.1 g. of 2-diethylaminoethyl (I d-d1 phenyl-m-toluate hydrochloride are obtained as a white, water-soluble powder melting at 141.0-142.5 C. It has the structural formula CaHt EXAIVIPLE 11 3-diethylaminopropyl ester of a,a-diphenyl-mtoluz'c acid m-toluic acid is obtained as 14.3 e. of a colorless syrup boiling at about 238247 C. and 0.5 mm.

pressure.

EXAMPLE 12 Z-diethylamz'noethyl ester of a,a-diphenyl-ptoluic acid To a refluxing solution of 28.8 g. of a,a-diphen yl-p-toluic acid in To a solution of 13 g. of the 2-diethylaminoethyl ester of a,a-diphenyl-p-to1uic acid in 1000 ml. of anhydrous ethyl ether are added 4.8 ml.

solution of hydrogen chloride in an- In this manner, 9.1 has a melting point C. are obtained. It has the structural formula CtHs EXAMPLE 13 a,a-Diphenyl-p-toluic acid ester of Z-hydrozy ethyltriethylammonium bromide A solution of 11.5 g. of the 2-diethylaminoethyl ester of a,a-diphenyl-p-toluic acid, 6.5 g. ofethyl concentration of the solvent, there are obtained 6.2 g. of colorless leaflets melting at 177178 C.

EXAMPLE 14 J-dlethylaminopropyl ester of a,a-diphenyl-ptoluic acid To a refluxing solution of 40 g. of a,-diphenylp-toluic acid in 500 ml. of isopropanol are added 21 g. of 3-diethylaminopropyl chloride in one batch. After refluxing the reaction mixture for a period of 4 hours, the isopropanol is removed by vacuum distillation on the steam bath. The residue is taken up in water and made alkaline with potassium hydroxide. The released oil is extracted with ether, and the extract is dried over anhydrous potassium carbonate. From the filtered, ether-stripped extract there are obtained 31 g. of colorless oil boiling at 248-260 C. and 0.6 mm. pressure.

To a solution of 15 g. of the Q-diethylaminopropyl ester of a,a-diphenyl-p-toluic acid in 1000 m1. of anhydrous ethyl ether are added 5.6 ml. of a 25% solution of hydrogen chloride in anhydrous isopropanol. The resultant hydrochloride is recrystallized from methyl ethyl ketone to give 13.5 g. of colorless rod-shaped crystals which melt at l63.5164.5 C.

EXAMPLE 15 a,a-Diphenyl-p-toluic acid ester of 3-hydroxypropyltriethylammonium bromide A solution of 12.5 g. of propyl ester of a,a-diphenyl-p-toluic acid, 68 g. of ethyl bromide and 20 ml. of methyl ethyl ketone is sealed in a shielded pressure bottle and heated on the steam bath for 3 hours. After preliminary cooling and pressure release, crystaL lization of the quaternary salt is induced by cooling in the icebox. The quaternary salt is filtered, washed with 100 m1. of methyl ethyl ketone and recrystallized from methyl ethyl ketone. A yield of 9.3 g. of white needles melting at 158.5-l59.5 C. is obtained.

EXAMPLE 16 Z-dimethylaminoethyl ester of a,a-di-o-tolyl-ptoluic acid A stirred refluxing solution of 31.6 of a,a-di o-tolyl-p-toiuic acid in 700 ml. of anhydrous isopropanol is treated with 13.5 g. of 2-dimethylaminoethyl chloride which is added in one batch. The reaction mixture is refluxed for 4 hours and the isopropanol distilled off under vacuum on the steam bath. The residue is taken up in water and sodium hydroxide is added until the solution becomes alkaline. An oil separates which is extracted with ether and the extract is dried over anhydrous potassium carbonate. The extract is filtered and upon evaporation, the oily z-dimethylaminoethyl ester of a,a,-di-o-tolyl-ptoluic acid is obtained. It is soluble in ether and inrelated solvents and forms crystalline salts with acids such as hydrochloric and hydrobromic acids.

EXAMPLE 1'! Z-(N-piperidino) ethyl ester of a,a-diphenyl-ptoluic acid 9.5 g. of 0.,a-dlPh8IlY1-P-t0lui0 acid in 200 ml. of anhydrous isopropanol are heated for hours with 4.8 g. of N- (fi-chloroethyl) piperidine. The isopropanol is distilled off under vacuum, and the residue is made alkaline by the addition of a strong aqueous solution of potassium hydroxide. The 2-(N-piperidino)ethyl ester of a,a-diphenylp-toluic acid is extracted with ether and the extract is dried over anhydrous potassium carthe B-diethylaminobonate.

00 0 camp are aromatic hydrocarbon radicals containing not more than 7 carbon atoms, Alk is a lower alkylene radical containing at least 2 carbon atoms and B is an amino radical selected from the class consisting oi di(lower alkyl) amino, morpholino, lupetidino, pyrrolidino and piperidino radicals.

2. A dialkylaminoalkyl ester of an a,a-diphenyltoluic acid, having the formula wherein Alk is a lower alkylene radical containing at least 2 carbon atoms and R. and R are lower alkyl radicals.

3. A di (lower alkyl) aminoethyl ester of an diphenyltoluic acid.

4. 2-diethylaminoethy1 a,a-diphenyl-otoluate.

5. A quaternary ammonium salt of a dialkyiaminoalkyl ester of an ,a-diphenyltoluic acid. having the formula wherein Ar and Ar wherein Alk is a lower alkylene radical containing at least 2 carbon atoms; R, R and R" are lower alkyl radicals and X is one equivalent of an anion.

6. A quaternary ammonium salt of 2-diethylaminoethyl a,a-diphenyl-o-toluate, having the formula wherein X is one equivalent of an anion.

'1. Z-diethylaminoethyl ,v.-diphenyl-o-toluate ethobromide.

8. A dialkylaminoalkyl ester of an ,a-ditolyltoluic acid, having the formula can-0H3 CHrr-CqHi-CH wherein All: is a lower alkylene radical containing at least 2 carbon atoms and R and R are lower alkyl radicals.

9. A di(lower alkyl) aminoethyl ester of an 0,. ditolyltoluic acid.

10. Z-diethylaminoethyl a,-di(o-toly1)-o-to1u- 14. A diethylaminopropyl ,a-dipheny1to1uate. ate. 15. Z-diethylaminopropyl a,a-dipheny1-o-tolu- 11. A piperidinoethyl a,adiphenyltoluate. ate.

12. p-(N-piperidinwethyl a,a-dipheny1-o-tolu- CARL PETER KRIMMEL. ate. 5

A dialkylamimpmpyl ester an References Cited in the file of this patent phenyltolmc havmg the formula Jones et aL: J. Am. Chem. $00., vol. 48, pp.

CIHB 181-195 (1926). am- H 10 Marvel et a1.: J. Am. Chem. Soc., vol. 63, pp.

2221-2222 (1941) COO-CnHc-NRR wherein R and R are lower alkyl radicals. 

1. A MEMBER OF THE CLASS OF COMPOUNDS CONSISTING OF A BASIC ESTER OF AN A,A-DIARYLTOLUIC ACID AND SALTS THEREOF, SAID BASIC ESTER HAVING THE FORMULA 